Alzheimer's disease (AD) is associated with progressive cognitive decline and the accumulation of senile plaques and neurofibrillary tangles. Senile plaques contain the beta-amyloid peptide (A[unreadable]), which is thought to play a causative role in the disease. Thus, a number of therapeutics are being developed that may reduce the production, deposition or enhance clearance of A[unreadable] in the brains of patients with AD. In transgenic mouse models of AD, deposition of A[unreadable] may be prevented or reduced after immunization with fibrillar A[unreadable]1-42. Further, learning and memory is improved by either active or passive immunization with anti-A[unreadable] antibodies. On the basis of work in transgenic mice, a clinical trial (AN1792) was initiated in AD patients who were administered fibrillar A[unreadable]42. Cognitive benefits were reported in this study and autopsy studies show a reduction in brain A[unreadable]. We extended immunotherapy studies into the canine model of human brain aging that naturally develop human-type A[unreadable] and cognitive decline. Aged animals were actively immunized for over 2 years (25 injections in total). Our results in immunized aged beagles showed decreased brain A[unreadable] and improved executive function. We hypothesize that we can improve cognition to a greater extent, and extend cognitive improvements to include multiple domains by combined treatment with an intervention that may restore neuron health after A[unreadable] removal. Thus we propose to combine immunotherapy with behavioral enrichment in aged dogs and target two molecular pathways that may converge to provide additive benefits. We predict aged dogs will show significant cognitive improvements, maintenance of cognition and reduced neuropathology when we combine immunotherapy with behavioral enrichment. Further, the combination treatment will provide larger benefits to cognition and neuropathology than either treatment alone. The canine provides a unique model system in which to develop combinatorial treatment approaches involving immunotherapy for reducing AD pathology and improving cognition that may be more directly translated into human clinical trials. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is associated with progressive cognitive decline and the accumulation of brain pathology. We will use a combination treatment approach to improve cognition and reduce neuropathology in the canine model of aging through immunotherapy and behavioral enrichment, which is an approach that may be directly translated into human clinical trials.